Preparation method of apixaban and intermediate thereof

Abstract

The invention provides a preparation method of an apixaban intermediate, which comprises the following steps: amidating a compound e and acyl chloride, and then carrying out cyclization reaction under the action of inorganic alkali to obtain a compound f, and the cyclization reaction is carried out in a mixed solution of an organic solvent and water. According to the method provided by the invention, the apixaban intermediate compound f can be prepared with high purity and high yield, and the reaction operation is simple, so that the method is very suitable for industrial production. # imgabs0 #

Description

Technical Field

[0001] The present invention specifically relates to the field of medicine, and relates to a method for preparing apixaban and an intermediate thereof. Technical Background

[0002] Apixaban, English name (Apixaban), chemical name is 1-(4-methoxyphenyl)-7-oxo-6[4-(2-oxopiperidin-1-yl)phenyl]-4,5,6,7-tetrahydro-1H-pyrazolo[3,4-c]pyridine-3-carboxamide. The structural formula of Apixaban is as follows:

[0003]

[0004] In the patent CN104045637B, it is mentioned that dichloromethane is used as a solvent, and compound I and compound II undergo [3+2] cyclization reaction in the presence of solid sodium carbonate and solid tetrabutylammonium bromide, and then continue to react under the action of acid. The organic layer is subjected to recrystallization and other operations to obtain solid compound C, with a yield of 82.5% to 89.9%; compound C undergoes reduction reaction under the action of iron powder, ammonium chloride, etc., and solid compound D is obtained after post-treatment, with a yield of 81.6% to 89.3%; compound D undergoes amidation reaction with 5-chlorovaleryl chloride under the conditions of triethylamine and anhydrous organic solvent, and the reaction is post-treated to obtain the amidation product shown in compound E, with a yield of 81.5% to 84.7%; the amidation product shown in compound E reacts with a solid strong base and a solid phase transfer catalyst in an anhydrous organic solvent, and the reaction is terminated and post-treated to obtain a solid compound F, with a yield of 82.7% to 88.3%. Compound G is then hydrolyzed and aminated to obtain apixaban. The synthetic route is as follows:

[0005] Summary of the invention

[0006] The object of the present invention is to provide an improved method for preparing apixaban and its intermediates.

[0007] The first aspect of the present invention provides a method for preparing an apixaban intermediate compound f, comprising the following steps (c): compound e undergoes an amidation reaction with an acyl chloride, and then undergoes a cyclization reaction in the presence of an inorganic base to obtain compound f, wherein the cyclization reaction is carried out in a mixed solution of an organic solvent and water, and the synthesis route is as follows:

[0008]

[0009] The acyl chloride is 5-chlorovaleryl chloride or 5-bromovaleryl chloride.

[0010] The second aspect of the present invention also provides a method for preparing apixaban, comprising the following steps (c) and (d):

[0011] Step (c): Compound e undergoes an amidation reaction with an acyl chloride, followed by a cyclization reaction to obtain compound f.

[0012]

[0013] Step (d): preparing compound f into apixaban;

[0014] The cyclization reaction is carried out in a mixed solution of an organic solvent and water, and the acyl chloride is 5-chlorovaleryl chloride or 5-bromovaleryl chloride.

[0015] According to a preferred embodiment of the present invention, the method of the first aspect or the method of the second aspect of the present invention further comprises the following step (b): compound d is reacted under the action of a reducing agent to obtain compound e,

[0016]

[0017] Further, according to a preferred embodiment of the present invention, the method of the first aspect or the method of the second aspect of the present invention further comprises the following steps (a): compound b and compound c undergo a [3+2] cyclization reaction under the action of a base, and then react with an acid to obtain compound d;

[0018]

[0019] The method of each step of the present invention will be described in detail below according to the reaction sequence:

[0020] Step (a):

[0021] Compound b and compound c undergo a [3+2] cyclization reaction under the action of a base, and then an acid is used to obtain compound d;

[0022]

[0023] According to a preferred embodiment of the present invention, the reaction system described in step (a) is carried out in a mixed solution of water and an organic solvent, and the organic solvent is preferably one or more of ethyl acetate, 2-methyltetrahydrofuran, toluene, xylene, chloroform, and dichloromethane. The amount of the organic solvent relative to compound (b) is preferably 2 to 10 ml / g, preferably 3 to 6 ml / g. The amount of water used is generally 0.5 to 30 ml / g, preferably 3 to 10 ml / g, and more preferably 3 to 5 ml / g per gram of compound b.

[0024] The present inventors unexpectedly found that by adding water as one of the reaction media in step (a), compound d can be obtained with higher purity and higher yield.

[0025] According to a preferred embodiment of the present invention, the step (a) [3+2] cyclization reaction is carried out in the presence of a phase transfer catalyst, and the phase transfer catalyst is preferably one or more of tetrabutylammonium hydrogen sulfate, tetrabutylammonium chloride, tetrabutylammonium bromide, tetrabutylammonium iodide, benzyltrimethylammonium chloride, benzyltrimethylammonium bromide, benzyltrimethylammonium iodide, benzyltriethylammonium chloride, benzyltriethylammonium bromide or benzyltriethylammonium iodide.

[0026] According to a preferred embodiment of the present invention, the molar ratio of the phase transfer catalyst to the compound b in the reaction system of step (a) is 0.001 to 5.0, preferably 0.03 to 1, for example 0.05, 0.1, 0.15, 0.2, 0.25, 0.3, 0.4, 0.5, 0.6, 0.8, 1 or any range therebetween.

[0027] According to a preferred embodiment of the present invention, the metal halide in step (a) can be selected from metal iodides or metal bromides, preferably sodium iodide, potassium iodide, cuprous iodide, and cuprous bromide.

[0028] According to a preferred embodiment of the present invention, the molar ratio of the metal halide to the compound b in step (a) is 0.1 to 10, preferably 0.15 to 1.0, for example 0.2, 0.3, 0.5, 0.8, 1 or a range of two values ​​thereof.

[0029] According to a preferred embodiment of the present invention, the reaction in step (a) is carried out in the presence of a base, and the base is selected from an inorganic base or an organic base. The inorganic base compound can be a widely used inorganic base type, including alkali metal hydroxides, such as sodium hydroxide, potassium hydroxide, lithium hydroxide, or alkali metal carbonates, such as sodium carbonate, potassium carbonate, lithium carbonate; the organic base can be selected from triethylamine, diethylamine, diisopropylethylamine, N-methylmorpholine, morpholine and pyridine. The type of the base can be one or more.

[0030] According to a preferred embodiment of the present invention, the molar ratio of the base in step (a) to compound b is 0.9-10, preferably 1-6, and more preferably 1-2.

[0031] According to a preferred embodiment of the present invention, the molar ratio of compound c to compound b in the reaction system of step (a) is 0.8-1.5, preferably 0.95-1.2, for example 0.95, 1, 1.05, 1.1, 1.2 or any value therebetween.

[0032] According to a preferred embodiment of the present invention, the reaction temperature in step (a) is generally 20°C to 90°C, for example 30°C, 35°C, 40°C, 45°C, 50°C, 55°C, 60°C, 65°C, 70°C, 75°C, 80°C, and the reaction time is generally 2h to 8h; preferably the reaction temperature is 35°C to 70°C, and the time is 3h to 6h.

[0033] According to a preferred embodiment of the present invention, the operation method of step (a) is to slowly add compound c to a mixed solution containing compound b, alkali, metal halide, water and organic solvent under heating conditions. By slowly adding the materials, compound c can react quickly with compound b, which can effectively reduce the condensation or degradation reaction of compound c under alkaline conditions.

[0034] According to a preferred embodiment of the present invention, after the [3+2] annulation reaction in step (a) is completed, the reaction is allowed to stand for separation and the aqueous phase is removed, which can effectively remove impurities and salts in the system and avoid post-treatment operations such as washing and desalting. Compared with a single organic solvent system or a solid-liquid mixed reaction system, the post-treatment operation of the two-phase reaction system is simpler and more convenient.

[0035] According to a preferred embodiment of the present invention, after the reaction in step (a) is completed, the reaction is allowed to stand and the separated organic phase is treated with an acid to obtain compound d, wherein the acid is hydrochloric acid, sulfuric acid or trifluoroacetic acid, preferably hydrochloric acid.

[0036] According to a preferred embodiment of the present invention, after the organic phase in step (a) is treated with acid, the reaction is allowed to stand for stratification to obtain an organic phase containing compound d, and the organic phase containing compound d is directly used in the reaction of step (b).

[0037] Step (b):

[0038] Compound d reacts with a reducing agent to obtain compound e. The synthesis route is as follows:

[0039]

[0040] According to a preferred embodiment of the present invention, the reducing agent in step (b) is selected from sodium hydrosulfide, sodium sulfide, stannous chloride, iron powder / ammonium chloride, and hydrazine hydrate.

[0041] According to a preferred embodiment of the present invention, the molar ratio of the reducing agent to compound b in step (b) is 1 to 8, preferably 0.5 to 5.0.

[0042] According to a preferred embodiment of the present invention, the reducing agent in step (b) is further preferably sodium hydrosulfide, and the molar ratio of the reducing agent to compound b is preferably 1 to 3.

[0043] According to a preferred embodiment of the present invention, water may be added to the reaction system of step (b) to dissolve the reducing agent. In a specific embodiment of the present invention, the reaction of step (b) is carried out in an organic solvent, and the organic solvent is the organic solvent added during step (a).

[0044] According to a preferred embodiment of the present invention, the reaction temperature in step (b) is generally 20°C to 95°C, for example 30°C, 35°C, 40°C, 45°C, 50°C, 55°C, 60°C, 65°C, 70°C, 75°C, 80°C, 95°C, and the reaction time is generally 2h to 12h; preferably, the reaction temperature is 35°C to 70°C, and the reaction time is 6h to 9h.

[0045] According to a preferred embodiment of the present invention, after the reduction reaction in step (b) is completed, the organic phase containing compound e is separated and directly used in the reaction in step (c).

[0046] Step (c):

[0047] Compound e undergoes an amidation reaction with an acyl chloride, and then undergoes a cyclization reaction under the action of an inorganic base to obtain compound f. The cyclization reaction is carried out in a mixed solution of an organic solvent and water. The synthesis route is as follows:

[0048]

[0049] The acyl chloride is 5-chlorovaleryl chloride or 5-bromovaleryl chloride.

[0050] According to a preferred embodiment of the present invention, the compound e in step (c) is contacted with the acyl chloride in an organic solvent to undergo an amidation reaction.

[0051] According to a preferred embodiment of the present invention, the base in the cyclization reaction of step (c) is selected from one or more of sodium hydroxide, potassium hydroxide and lithium hydroxide.

[0052] According to a preferred embodiment of the present invention, after the amidation reaction in step (c) is completed, an inorganic base and water are added to the reaction system to carry out a cyclization reaction.

[0053] The present inventors have found that after compound e is amidated with acyl chloride, the amidated product is cyclized in an aqueous alkaline system, and the purity of the obtained compound f can be significantly improved.

[0054] According to a preferred embodiment of the present invention, the molar ratio of the base in the cyclization reaction of step (c) to compound b is 0.9-10, preferably 1-3.

[0055] According to a preferred embodiment of the present invention, the cyclization reaction system described in step (c) contains a phase transfer catalyst, and the phase transfer catalyst is preferably one or more of tetrabutylammonium hydrogen sulfate, tetrabutylammonium chloride, tetrabutylammonium bromide, tetrabutylammonium iodide, benzyltrimethylammonium chloride, benzyltrimethylammonium bromide, benzyltrimethylammonium iodide, benzyltriethylammonium chloride, benzyltriethylammonium bromide, and benzyltriethylammonium iodide.

[0056] According to a preferred embodiment of the present invention, the molar ratio of the phase transfer catalyst to compound b in step (c) is 0.001-5.0, preferably 0.03-1, for example 0.05, 0.1, 0.15, 0.2, 0.25, 0.3, 0.4, 0.5, 0.6, 0.8, 1 or any range therebetween.

[0057] According to a preferred embodiment of the present invention, in the mixed solution of water and organic solvent in step (c), the organic solvent is one or more of ethyl acetate, 2-methyltetrahydrofuran, toluene, xylene, chloroform and dichloromethane.

[0058] According to a preferred embodiment of the present invention, the amount of water used in step (c) is 0.5 to 30 ml / g, preferably 2 ml to 10 ml, per gram of compound b.

[0059] The organic solvent in step (c) is 2 ml to 10 ml, preferably 3 to 6 ml / g, per gram of compound b. In a specific embodiment of the present invention, they are all organic solvents added during step (a).

[0060] In some embodiments, the reaction temperature in step (c) is generally 20°C to 95°C, for example 30°C, 35°C, 40°C, 45°C, 50°C, 55°C, 60°C, 65°C, 70°C, 75°C, 80°C, 90°C, and the reaction time is generally 2h to 20h; preferably, the reaction temperature is 35°C to 70°C, and the reaction time is 5h to 6h.

[0061] According to a preferred embodiment of the present invention, after the cyclization reaction in step (c) is completed, compound f can be isolated by conventional post-treatment methods.

[0062] According to a preferred embodiment of the present invention, after the ring-closure reaction in step (c) is completed, the organic phase is separated by standing and stratification, and an anti-solvent is added to the organic phase, the temperature is lowered for crystallization, and the compound F is obtained by filtration. The anti-solvent is selected from one or more of petroleum ether, cyclohexane, n-hexane, n-heptane, isoheptane, methyl tert-butyl ether, ethyl ether, and isopropyl ether, preferably n-heptane.

[0063] Step (d):

[0064] Compound f is prepared into apixaban;

[0065]

[0066] Compound f can be converted to apixaban according to the schemes disclosed in the prior art, for example, by reacting compound f with ammonia in a suitable solvent to produce apixaban, which is isolated and optionally crystallized.

[0067] According to the method provided by the present invention, the apixaban intermediate compound f can be prepared with high purity and high yield, and the reaction operation is simple, no special requirements are placed on equipment, and the method is very suitable for large-scale industrial production. BRIEF DESCRIPTION OF THE DRAWINGS

[0068] Figure 1 The high performance liquid chromatography (HPLC) test result of compound f in Example 1 is shown in FIG.

[0069] Figure 2 The high performance liquid chromatography (HPLC) test result of compound f in comparative example 1 is shown in FIG. DETAILED DESCRIPTION

[0070] The following specific preparation examples are intended to illustrate the present invention in detail. The examples are only used for more detailed and specific description, and are not intended to limit the present invention in any form.

[0071] The high performance liquid chromatography (HPLC) conditions for detecting compound f in the embodiment of the present invention are:

[0072] Instrument: High performance liquid chromatography equipped with UV detector

[0073] Chromatographic column: Agilent ZORBAX SB C18 150×3.0mm, 3.5μm

[0074] Mobile phase A: 1.156 g ammonium acetate dissolved in 1000 ml water

[0075] Mobile phase B: acetonitrile

[0076] Detection wavelength: 280nm Flow rate: 1.0ml / min Injection volume: 10 μl

[0077] Column temperature: 35°C Run time: 32 minutes

[0078] Gradient table:

[0079] Time (minutes) Mobile phase A (% V / V) Mobile phase B (% V / V) 0 90 10 22 40 60 24 20 80 26 90 10 32 90 10

[0080] Example 1

[0081] Add 80 ml of an aqueous solution containing 9.1 g of potassium carbonate, 0.5 g of benzyltrimethylammonium bromide and 5.9 g of sodium iodide to 70 ml of an ethyl acetate solution containing 20.0 g of compound b. Slowly add 30 ml of an ethyl acetate solution containing 16.1 g of compound c to the reaction system under heating reflux for 4 hours. After the addition is completed, cool the system, let it stand to separate the organic phase, slowly add 50 ml of 15% dilute hydrochloric acid to the organic phase, and react for 0.5 hour. After the reaction is completed, separate the organic phase containing compound d.

[0082] 7.4 g of sodium hydrosulfide and 40 ml of drinking water were added to the organic phase containing compound d, and the reaction was refluxed for 7 h. After the reduction reaction was completed, the mixture was allowed to stand for stratification and the aqueous phase was separated to obtain an organic phase containing compound e.

[0083] 20.4 g of 5-chlorovaleryl chloride was added dropwise to the organic phase containing compound e, and compound e reacted with the acyl chloride to undergo an amidation reaction, and the amidation reaction was completed; 100 ml of an aqueous solution containing 2.6 g of sodium hydroxide and 0.9 g of benzyltrimethylammonium bromide was added to the organic phase, and the reaction was refluxed for 5 h. After the reaction was completed, the mixture was allowed to stand for stratification again and the aqueous phase was separated. 300 ml of petroleum ether was added dropwise to the organic phase under stirring, and the mixture was cooled to 5° C. for crystallization, filtered, and dried to obtain 26.2 g of compound f, with a three-step comprehensive yield of 81.2% (relative to compound b) and an HPLC purity of 99.1%.

[0084] Example 2

[0085] Add 1000 ml of an aqueous solution containing 104.8 g of sodium carbonate, 36.5 g of tetrabutylammonium iodide and 32.8 g of potassium iodide to 500 ml of a dichloromethane solution containing 200.0 g of compound b. Slowly add 100 ml of a dichloromethane solution containing 194.6 g of compound c to the reaction system under heating and reflux. The addition time is 6 hours. After the addition is completed, cool the mixture, let it stand to separate the layers and separate the organic phase. Slowly add a mixed solution of 300 g of trifluoroacetic acid and 100 ml of water to the organic phase. React for 0.5 hours. After the reaction is completed, separate the organic phase containing compound d.

[0086] 154.4 g of sodium sulfide and 200 ml of drinking water were added to the organic phase containing compound d, and the mixture was refluxed for 6 h. After the reduction reaction was completed, the mixture was allowed to stand for separation and the aqueous phase was removed to obtain an organic phase containing compound e.

[0087] 255.5 g of 5-chlorovaleryl chloride was added dropwise to the organic phase containing compound e, and compound e and the acyl chloride underwent an amidation reaction, and the amidation reaction was completed; 600 ml of an aqueous solution containing 62.9 g of potassium hydroxide and 21.9 g of tetrabutylammonium iodide was added to the organic phase, and the reaction was refluxed for 5 h. After the reaction was completed, the mixture was allowed to stand for stratification again and the aqueous phase was separated. 3.2 L of n-hexane was added dropwise to the organic phase under stirring, and the mixture was cooled to 3° C. for crystallization, filtered, and dried to obtain 259 g of compound f, with a three-step comprehensive yield of 80.4% (relative to compound b) and an HPLC purity of 99.1%.

[0088] Example 3

[0089] Add 3L of aqueous solution containing 203g of potassium hydroxide, 90g of tetrabutylammonium hydrogen sulfate and 371g of sodium iodide to 3L of chloroform solution containing 1.0kg of compound b, and slowly drop 1L of chloroform solution containing 838g of compound c into the reaction system under heating reflux for 4h. After the addition is completed, cool, stand to separate the layers and separate the organic phase. Slowly add 3.3L of 15% dilute hydrochloric acid into the organic phase and react for 0.5h. After the reaction is completed, separate the organic phase containing compound d.

[0090] 278 g of sodium hydrosulfide and 600 ml of drinking water were added to the organic phase containing compound d, and the mixture was refluxed for 6 h. After the reduction reaction was completed, the mixture was allowed to stand for separation and the aqueous phase was removed to obtain an organic phase containing compound e.

[0091] 920 g of 5-chlorovaleryl chloride was added dropwise to the organic phase containing compound e, and compound e and the acyl chloride underwent an amidation reaction, and the amidation reaction was completed; 2 L of an aqueous solution containing 222 g of potassium hydroxide and 134 g of tetrabutylammonium hydrogen sulfate was added to the organic phase, and the reaction was refluxed for 6 h. After the reaction was completed, the mixture was allowed to stand for stratification again and the aqueous phase was separated. 14 L of ether was added dropwise to the organic phase under stirring, and the mixture was cooled to 2 ° C for crystallization, filtered, and dried to obtain 1.31 kg of compound f, with a three-step comprehensive yield of 81.2% (relative to compound b) and an HPLC purity of 99.0%.

[0092] Example 4

[0093] A 1000 ml aqueous solution containing 147.3 g of benzyltriethylammonium iodide, 300 g of morpholine and 18.8 g of cuprous iodide was added to a 700 ml 2-methyltetrahydrofuran solution containing 200.0 g of compound b. Under heating and reflux, a 300 ml 2-methyltetrahydrofuran solution containing 174.3 g of compound c was slowly added dropwise to the reaction system for 6 h. After the addition was completed, the mixture was cooled, allowed to stand for stratification and the organic phase was separated. 1 L of 20% dilute sulfuric acid was slowly added to the organic phase and the reaction was carried out for 0.5 h. After the reaction was completed, the organic phase containing compound d was separated.

[0094] 206.3 g of hydrazine hydrate and 360 ml of drinking water were added to the organic phase containing compound d, and the mixture was refluxed for 6 h. After the reduction reaction was completed, the mixture was allowed to stand for stratification and the aqueous phase was separated to obtain an organic phase containing compound e.

[0095] 122.6 g of 5-chlorovaleryl chloride was added dropwise to the organic phase containing compound e, and compound e and the acyl chloride underwent an amidation reaction, and the amidation reaction was completed; 1.4 L of an aqueous solution containing 29.4 g of lithium hydroxide and 73.3 g of tetrabutylammonium chloride was added to the organic phase, and the reaction was refluxed for 5 h. After the reaction was completed, the mixture was allowed to stand for stratification again and the aqueous phase was separated. 2 L of n-heptane was added dropwise to the organic phase under stirring, and the temperature was lowered to 6° C. for crystallization, filtered, and dried to obtain 253.5 g of compound f, with a three-step comprehensive yield of 78.7% (relative to compound b) and an HPLC purity of 98.6%.

[0096] Example 5

[0097] Add 600 ml of an aqueous solution containing 55 g of tetrabutylammonium chloride, 86.8 g of diethylamine and 39.5 g of sodium iodide to 400 ml of a xylene solution containing 200.0 g of compound b. Slowly add 300 ml of a xylene solution containing 155.7 g of compound c to the reaction system under heating and reflux. The addition time is 6 hours. After the addition is completed, cool, stand to separate the layers and separate the organic phase. Slowly add 1.6 L of 10% dilute sulfuric acid to the organic phase and react for 1 hour. After the reaction is completed, separate the organic phase containing compound d.

[0098] 595.1 g of stannous chloride and 600 ml of drinking water were added to the organic phase containing compound d, and the mixture was refluxed for 7 h. After the reduction reaction was completed, the mixture was allowed to stand for separation and the aqueous phase was removed to obtain an organic phase containing compound e.

[0099] 163.5 g of 5-chlorovaleryl chloride was added dropwise to the organic phase containing compound e, and compound e reacted with the acyl chloride to undergo an amidation reaction, and the amidation reaction was completed; 0.8 L of an aqueous solution containing 66 g of sodium hydroxide and 98 g of benzyltrimethylammonium chloride was added to the organic phase, and the reaction was refluxed for 6 h. After the reaction was completed, the mixture was allowed to stand for stratification again and the aqueous phase was separated. 6 L of cyclohexane was added dropwise to the organic phase under stirring, and the mixture was cooled to 4 ° C for crystallization, filtered, and dried to obtain 264.6 g of compound f, with a three-step comprehensive yield of 82.2% (relative to compound b) and an HPLC purity of 99.1%.

[0100] Comparative Example 1:

[0101] The organic phase of compound e was obtained by referring to the method of Example 1; 20.4 g of 5-chlorovaleryl chloride was added dropwise to the organic phase containing compound e, and compound e and the acyl chloride were amidated, and the amidation reaction was completed; 2.6 g of sodium hydroxide solid and 0.9 g of benzyltrimethylammonium bromide were added to the organic phase, and the reaction was refluxed for 5 h. TLC detected that the raw materials had reacted completely. 300 ml of petroleum ether was added dropwise to the reaction solution under stirring, and the temperature was lowered to 5°C for crystallization, filtered, and dried to obtain 22.7 g of compound f. The comprehensive yield of the three steps was 70.5% (relative to compound b), and the HPLC purity was 95.6%.

Claims

1. A method for preparing an apixaban intermediate f, characterized in that: The method comprises the following step (c): compound e undergoes an amidation reaction with an acyl chloride, and then undergoes a cyclization reaction in the presence of an inorganic base to obtain compound f. The cyclization reaction is carried out in a mixed solution of an organic solvent and water. The synthesis route is as follows: The acyl chloride is 5-chlorovaleryl chloride or 5-bromovaleryl chloride.

2. A method for preparing apixaban, characterized in that: The method comprises the following steps (c) and (d): Step (c): Compound e undergoes an amidation reaction with an acyl chloride, and then undergoes a cyclization reaction in the presence of an inorganic base to obtain compound f. The cyclization reaction is carried out in a mixed solution of an organic solvent and water. The acyl chloride is 5-chlorovaleryl chloride or 5-bromovaleryl chloride. The synthetic route is as follows: Step (d): preparing compound f into apixaban.

3. The preparation method according to claim 1 or 2, characterized in that: The method further comprises the following step (b): compound d is reacted with a reducing agent to obtain compound e, 4. The preparation method according to claim 3, characterized in that The method further comprises the following step (a): compound b and compound c undergo a [3+2] cyclization reaction under the action of a base, and then an acid is used to obtain compound d; the synthetic route is as follows:

5. The preparation method according to claim 4, characterized in that: The reaction system of step (a) is carried out in a mixture of water and an organic solvent in the presence of a phase inversion catalyst; Further, the phase transfer catalyst in step (a) is preferably one or more of tetrabutylammonium hydrogen sulfate, tetrabutylammonium chloride, tetrabutylammonium bromide, tetrabutylammonium iodide, benzyltrimethylammonium chloride, benzyltrimethylammonium bromide, benzyltrimethylammonium iodide, benzyltriethylammonium chloride, benzyltriethylammonium bromide or benzyltriethylammonium iodide, and the organic solvent is preferably one or more of ethyl acetate, 2-methyltetrahydrofuran, toluene, xylene, chloroform and dichloromethane; Furthermore, a metal halide is also added in step (a); preferably, the metal halide is a metal iodide or a metal bromide, more preferably sodium iodide, potassium iodide, cuprous iodide or cuprous bromide.

6. The preparation method according to claim 5, characterized in that: After the [3+2] cyclization reaction in step (a) is completed, the layers are allowed to stand, the aqueous phase is removed, and the organic phase is separated to obtain the organic phase, which is treated with an acid to obtain compound d, wherein the acid is preferably hydrochloric acid, sulfuric acid or trifluoroacetic acid; after the organic phase in step (a) is treated with an acid, the layers are allowed to stand, and the organic phase containing compound d is separated to obtain the organic phase, which is directly used in the reaction in step (b).

7. The preparation method according to claim 3, characterized in that: The reducing agent described in step (b) is sodium hydrosulfide, sodium sulfide, stannous chloride, iron powder / ammonium chloride, hydrazine hydrate; Furthermore, after the reduction reaction in step (b) is completed, the organic phase containing compound e is separated and directly used in the reaction in step (c).

8. The preparation method according to claim 1 or 2, characterized in that: In the step (c), compound e is contacted with 5-chlorovaleryl chloride in an organic solvent to undergo an amidation reaction. After the amidation reaction is completed, an inorganic base and water are added to the reaction system to carry out a cyclization reaction. The base is preferably one or more of sodium hydroxide, potassium hydroxide, and lithium hydroxide.

9. The preparation method according to claim 1 or 2, characterized in that: The cyclization reaction system of step (c) comprises a phase transfer catalyst, and the phase transfer catalyst is preferably one or more of tetrabutylammonium hydrogen sulfate, tetrabutylammonium chloride, tetrabutylammonium bromide, tetrabutylammonium iodide, benzyltrimethylammonium chloride, benzyltrimethylammonium bromide, benzyltrimethylammonium iodide, benzyltriethylammonium chloride, benzyltriethylammonium bromide, and benzyltriethylammonium iodide; Furthermore, the organic solvent for the cyclization in step (c) is one or more of ethyl acetate, 2-methyltetrahydrofuran, toluene, xylene, chloroform and dichloromethane.

10. The preparation method according to claim 4, characterized in that: The amount of water used in step (c) is 0.5 to 30 ml / g, preferably 2 to 10 ml, relative to each gram of compound b; the amount of the organic solvent used in the reaction system is 2 to 10 ml / g, preferably 3 to 6 ml / g, relative to compound (b); Furthermore, the reaction temperature of the cyclization reaction in step (c) is 20°C to 95°C, and the time is 2h to 20h; preferably, the reaction temperature is 35°C to 70°C, and the time is 5h to 6h.

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